Medical hypotheses最新文献

英文中文

Targeting the hypothalamic MC4 receptor: A novel approach to senolytic therapy?

IF 2.1 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2025-02-01 DOI: 10.1016/j.mehy.2024.111551

Youn Ju Kim, Joo Hyun Lim, Eun Ran Kim

The hypothalamus is a center of whole-body energy metabolism. With aging, its function decreases, leading to a higher chance of metabolic disorders. Conversely, overnutrition, such as in cases of type 2 diabetes and obesity, can also cause cellular senescence independent of age. Elevated glucose levels accelerate neuronal senescence by inducing oxidative stress and inflammatory responses, leading to cellular aging and neurodegeneration. Melanocortin receptor 4 (MC4R) neurons in the hypothalamus play a crucial role in energy homeostasis, and MC4R expression levels tend to decrease with aging. In our study, we exposed a mouse hypothalamic cell line (mHypoE-N46) to high glucose (50 mM) and observed an increase in the levels of the cellular senescence marker p21, along with a reduction in Mc4r levels. Additionally, we found an increase in Basic helix-loop-helix ARNT-like protein 1(Bmal1) expression, indicating a disruption of circadian rhythm in energy homeostasis regulated by the hypothalamus. Therefore, we hypothesize that: i) High glucose elevates Bmal1 in hypothalamic neurons, triggering senescence, which then downregulates MC4R. This leads to metabolic dysfunction and aging-independent metabolic abnormalities. ii) To ameliorate the senescence, agonizing MC4R signaling could be an option, potentially reducing p21 expression and normalizing Bmal1 expression rhythms in the hypothalamus. Besides, these agonists could also serve as senolytic therapeutics for correcting neuronal dysfunction in age-related metabolic regulation. Given the decreased levels of MC4R during aging, these agonists could be useful not only for senescence caused by overnutrition but also in natural aging processes. These hypotheses can be demonstrated using an animal model with high glucose or high-fat diet and hypothalamic-specific MC4R knockout mice. Understanding the mechanisms underlying biological age-independent senescence is crucial for identifying novel therapeutic targets and interventions to mitigate age-related diseases and promote healthy aging. The exploration of MC4R agonism as a senolytic approach could provide valuable insights into novel therapeutic avenues for combating age-related disorders and extending healthspan.

{"title":"Targeting the hypothalamic MC4 receptor: A novel approach to senolytic therapy?","authors":"Youn Ju Kim, Joo Hyun Lim, Eun Ran Kim","doi":"10.1016/j.mehy.2024.111551","DOIUrl":"10.1016/j.mehy.2024.111551","url":null,"abstract":"<div><div>The hypothalamus is a center of whole-body energy metabolism. With aging, its function decreases, leading to a higher chance of metabolic disorders. Conversely, overnutrition, such as in cases of type 2 diabetes and obesity, can also cause cellular senescence independent of age. Elevated glucose levels accelerate neuronal senescence by inducing oxidative stress and inflammatory responses, leading to cellular aging and neurodegeneration. Melanocortin receptor 4 (MC4R) neurons in the hypothalamus play a crucial role in energy homeostasis, and MC4R expression levels tend to decrease with aging. In our study, we exposed a mouse hypothalamic cell line (mHypoE-N46) to high glucose (50 mM) and observed an increase in the levels of the cellular senescence marker <em>p21</em>, along with a reduction in <em>Mc4r</em> levels. Additionally, we found an increase in Basic helix-loop-helix ARNT-like protein 1(<em>Bmal1</em>) expression, indicating a disruption of circadian rhythm in energy homeostasis regulated by the hypothalamus. Therefore, we hypothesize that: i) High glucose elevates <em>Bmal1</em> in hypothalamic neurons, triggering senescence, which then downregulates MC4R. This leads to metabolic dysfunction and aging-independent metabolic abnormalities. ii) To ameliorate the senescence, agonizing MC4R signaling could be an option, potentially reducing <em>p21</em> expression and normalizing <em>Bmal1</em> expression rhythms in the hypothalamus. Besides, these agonists could also serve as senolytic therapeutics for correcting neuronal dysfunction in age-related metabolic regulation. Given the decreased levels of MC4R during aging, these agonists could be useful not only for senescence caused by overnutrition but also in natural aging processes. These hypotheses can be demonstrated using an animal model with high glucose or high-fat diet and hypothalamic-specific MC4R knockout mice. Understanding the mechanisms underlying biological age-independent senescence is crucial for identifying novel therapeutic targets and interventions to mitigate age-related diseases and promote healthy aging. The exploration of MC4R agonism as a senolytic approach could provide valuable insights into novel therapeutic avenues for combating age-related disorders and extending healthspan.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111551"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148412","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hypothesized molecular mechanism of formation of membrano-cystic lesions

IF 2.1 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2025-02-01 DOI: 10.1016/j.mehy.2024.111561

Toshitsugu Nakamura

Membrano-cystic lesions (MCLs) are characterized by undulating lipomembranous changes of lipid droplets and usually found in atherosclerotic lesions of aorta/arteries or in adipose tissues associated with panniculitis. MCLs are composed of lipid-carbohydrate-protein complexes (LCPCs), stable even in paraffin-embedded tissue sections, and are histochemically similar, but not identical, to lipofuscin and ceroid. Lipid peroxides damage carbohydrates and proteins, generating advanced glycation end products and advanced oxidative protein products that may play an important role in the formation of MCLs and lipofuscin/ceroid; MCLs are formed by deposition of oxidative LCPCs into lipid droplet membranes. The author proposes a speculative hypothesis that these deposits may change membrane stiffness/fluidity and impair lipid efflux/influx in various kinds of degree by a part, resulting in deformation of lipid droplets and MCL formation. As membrane stiffness/fluidity in unaffected cells varies according to cholesterol concentration or saturated/unsaturated form of lipids, qualitive/quantitative variety of molecular components of the droplets may contribute to the deformability to lipid droplets.

{"title":"Hypothesized molecular mechanism of formation of membrano-cystic lesions","authors":"Toshitsugu Nakamura","doi":"10.1016/j.mehy.2024.111561","DOIUrl":"10.1016/j.mehy.2024.111561","url":null,"abstract":"<div><div>Membrano-cystic lesions (MCLs) are characterized by undulating lipomembranous changes of lipid droplets and usually found in atherosclerotic lesions of aorta/arteries or in adipose tissues associated with panniculitis. MCLs are composed of lipid-carbohydrate-protein complexes (LCPCs), stable even in paraffin-embedded tissue sections, and are histochemically similar, but not identical, to lipofuscin and ceroid. Lipid peroxides damage carbohydrates and proteins, generating advanced glycation end products and advanced oxidative protein products that may play an important role in the formation of MCLs and lipofuscin/ceroid; MCLs are formed by deposition of oxidative LCPCs into lipid droplet membranes. The author proposes a speculative hypothesis that these deposits may change membrane stiffness/fluidity and impair lipid efflux/influx in various kinds of degree by a part, resulting in deformation of lipid droplets and MCL formation. As membrane stiffness/fluidity in unaffected cells varies according to cholesterol concentration or saturated/unsaturated form of lipids, qualitive/quantitative variety of molecular components of the droplets may contribute to the deformability to lipid droplets.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111561"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Vitamin D mitigates soluble endoglin levels in preeclampsia by regulating sphingomyelin/ ceramide content of the placental exosome

IF 2.1 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2025-02-01 DOI: 10.1016/j.mehy.2024.111556

Juhi Nema, Sadhana Joshi

Vitamin D deficiency is associated with increased risk of preeclampsia. Vitamin D influences angiogenesis in preeclampsia, however the underlying mechanism remains unclear. Placental exosomes are released in the maternal circulation as early as the 6th week of gestation and its levels are reported to be increased in preeclampsia. Similarly, changes in the placental exosome cargo (increased sphingomyelin (SM) content) has also been reported in women with preeclampsia. Endoglin, an anti-angiogenic marker, has an affinity for SM-18:0 enriched microdomains which when released into the maternal circulation may lead to endothelial dysfunction. Our earlier studies in preeclampsia reports that alterations in the levels of angiogenic markers predate clinical diagnosis of preeclampsia. We have also reported that maternal vitamin D status influence fatty acid levels and their metabolism. It has been reported that vitamin D influences sphingolipid metabolism pathway and increases ceramide levels in the exosome bilayer. It is likely that vitamin D levels influence sphingomyelinase activity thereby affecting composition of sphingolipids and ceramides in exosomes and their release into the maternal circulation. Since, SM-18:0-enriched exosomes are associated with increased endoglin levels (in the exosomal cargo); it is possible that vitamin D influences angiogenesis by regulating the content of lipids in exosomes. We hypothesize that lower maternal vitamin D levels will increase sphingomyelin content in the exosomal bilayer resulting in increased endoglin cargo in the placental exosome which will be released into the maternal circulation. This will subsequently lead to impaired angiogenesis and endothelial dysfunction in preeclampsia.

{"title":"Vitamin D mitigates soluble endoglin levels in preeclampsia by regulating sphingomyelin/ ceramide content of the placental exosome","authors":"Juhi Nema, Sadhana Joshi","doi":"10.1016/j.mehy.2024.111556","DOIUrl":"10.1016/j.mehy.2024.111556","url":null,"abstract":"<div><div>Vitamin D deficiency is associated with increased risk of preeclampsia. Vitamin D influences angiogenesis in preeclampsia, however the underlying mechanism remains unclear. Placental exosomes are released in the maternal circulation as early as the 6th week of gestation and its levels are reported to be increased in preeclampsia. Similarly, changes in the placental exosome cargo (increased sphingomyelin (SM) content) has also been reported in women with preeclampsia. Endoglin, an anti-angiogenic marker, has an affinity for SM-18:0 enriched microdomains which when released into the maternal circulation may lead to endothelial dysfunction. Our earlier studies in preeclampsia reports that alterations in the levels of angiogenic markers predate clinical diagnosis of preeclampsia. We have also reported that maternal vitamin D status influence fatty acid levels and their metabolism. It has been reported that vitamin D influences sphingolipid metabolism pathway and increases ceramide levels in the exosome bilayer. It is likely that vitamin D levels influence sphingomyelinase activity thereby affecting composition of sphingolipids and ceramides in exosomes and their release into the maternal circulation. Since, SM-18:0-enriched exosomes are associated with increased endoglin levels (in the exosomal cargo); it is possible that vitamin D influences angiogenesis by regulating the content of lipids in exosomes. We hypothesize that lower maternal vitamin D levels will increase sphingomyelin content in the exosomal bilayer resulting in increased endoglin cargo in the placental exosome which will be released into the maternal circulation. This will subsequently lead to impaired angiogenesis and endothelial dysfunction in preeclampsia.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"195 ","pages":"Article 111556"},"PeriodicalIF":2.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143148429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Radioimmunotherapy in glioblastoma multiforme: A hypothesis to benefit immune effects of radiotherapy with full potential

IF 2.1 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2025-01-31 DOI: 10.1016/j.mehy.2025.111582

Can Ilgın, Rasim Meral

Glioblastoma multiforme (GBM) is the most common primary brain tumor with a 5-year median survival below 5%, despite the presence of multiple treatment modalities, including surgery, chemotherapy, radiotherapy, and immunotherapy. Tumor cells employ multiple mechanisms for evading immune system and GBM tumor microenvironment with immunosuppressive properties, and the use of immunotherapy is limited. Higher radiotherapy doses on target volumes increases neo-antigen formation, and blood brain barrier permeability. In this article, we hypothesized that lower radiation doses received by immune system tissues interacting with GBM, including cervical lymph nodes, lymphatic vessels, and bone marrow, may prevent the loss of immune system cells and disruption of immune system functions. A careful planed radiotherapy by considering immune system as an “organ at risk” may increase the immunotherapy efficiency, and overall survival in GBM patients.

引用次数: 0

A novel hypothesis about abnormalities in ependymal ciliary cytoskeleton driving the development of syringomyelia-associated scoliosis and its potential mechanism

IF 2.1 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2025-01-31 DOI: 10.1016/j.mehy.2025.111581

Chunli Lu , Min Yin , Xingwen Wang , Fengzeng Jian

Syringomyelia is a chronic progressive disorder characterized by a fluid-filled syrinx inside the spinal cord that is frequently accompanied by scoliosis. As a prevalent type of neuromuscular scoliosis, the proper therapy for syringomyelia-associated scoliosis (SAS) is still under dispute. Many possible hypotheses have been proposed in the past, but the exact mechanism of how SAS occurs and progresses remains unknown. It is known that idiopathic scoliosis might have a neurological etiology involving bilateral asymmetric neural signal abnormalities in synaptic neurotransmission. Previous studies have shown that its etiology begins in the early stages of pathology, with abnormal cerebrospinal fluid (CSF) circulation in the subarachnoid space due to ependymal polarity deviation and ciliary beating disorder. Abnormal ependymal polarity and ciliary disorder are also core factors during the progression of syringomyelia. Therefore, this study proposes a novel hypothesis implicating abnormalities in the ependymal ciliary cytoskeleton as a driving factor in the development of SAS. Specifically, the underlying factors disturb the circulation of the CSF, which in turn leads to disorder of ependymal cellular polarity and the Actin network, with centrioles and cilia falling off under the shear stress of the CSF. On the one hand, CSF accumulates abnormally in the central canal, resulting in syringomyelia. On the other hand, abnormal ciliary motility fails to maintain normal assembly of Reissner fibers, which could affect the transmission of certain important neurotransmitters and destroy the left and right sides’ periodic alternating neuronal activity, eventually leading to the occurrence of spinal deformities related to syringomyelia. A novel perspective on the pathophysiology of SAS is presented with the possible mechanism of ependymal ciliary dynamics modulating the direction of the body axis under pathological conditions. These findings could also help orient future research and therapy.

{"title":"A novel hypothesis about abnormalities in ependymal ciliary cytoskeleton driving the development of syringomyelia-associated scoliosis and its potential mechanism","authors":"Chunli Lu , Min Yin , Xingwen Wang , Fengzeng Jian","doi":"10.1016/j.mehy.2025.111581","DOIUrl":"10.1016/j.mehy.2025.111581","url":null,"abstract":"<div><div>Syringomyelia is a chronic progressive disorder characterized by a fluid-filled syrinx inside the spinal cord that is frequently accompanied by scoliosis. As a prevalent type of neuromuscular scoliosis, the proper therapy for syringomyelia-associated scoliosis (SAS) is still under dispute. Many possible hypotheses have been proposed in the past, but the exact mechanism of how SAS occurs and progresses remains unknown. It is known that idiopathic scoliosis might have a neurological etiology involving bilateral asymmetric neural signal abnormalities in synaptic neurotransmission. Previous studies have shown that its etiology begins in the early stages of pathology, with abnormal cerebrospinal fluid (CSF) circulation in the subarachnoid space due to ependymal polarity deviation and ciliary beating disorder. Abnormal ependymal polarity and ciliary disorder are also core factors during the progression of syringomyelia. Therefore, this study proposes a novel hypothesis implicating abnormalities in the ependymal ciliary cytoskeleton as a driving factor in the development of SAS.Specifically, the underlying factors disturb the circulation of the CSF, which in turn leads to disorder of ependymal cellular polarity and the Actin network, with centrioles and cilia falling off under the shear stress of the CSF. On the one hand, CSF accumulates abnormally in the central canal, resulting in syringomyelia. On the other hand, abnormal ciliary motility fails to maintain normal assembly of Reissner fibers, which could affect the transmission of certain important neurotransmitters and destroy the left and right sides’ periodic alternating neuronal activity, eventually leading to the occurrence of spinal deformities related to syringomyelia. A novel perspective on the pathophysiology of SAS is presented with the possible mechanism of ependymal ciliary dynamics modulating the direction of the body axis under pathological conditions. These findings could also help orient future research and therapy.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"196 ","pages":"Article 111581"},"PeriodicalIF":2.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143158294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The “conflict avoidance theory of inflammation-induced anxiety” (CATIA): A psychoneuroimmunologic hypothesis

IF 2.1 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2025-01-30 DOI: 10.1016/j.mehy.2025.111580

P.A. Nelles , N. Singewald , B. Sperner-Unterweger , K. Hüfner

Anxiety and inflammation are complex, interconnected physiological processes. The “Conflict Avoidance Theory of Inflammation-Induced Anxiety” (CATIA) hypothesizes that inflammation-induced anxiety confers an evolutionary advantage by promoting harm-avoidance and recovery-promoting behaviour. Inflammatory cytokines act as signalling molecules to anxiety-related brain regions, primarily limbic structures such as the amygdala, thus influencing decision-making and behaviour. This is archieved by priming these structures for exaggerated fear-responses counteracting conflict engagement, when adaptive physiological readiness is impaired.

This adaptive mechanism prioritizes recovery and survival during illness or injury. However, in modern contexts, inflammation driven by lifestyle factors or chronic conditions may perpetuate anxiety symptoms, contributing to psychiatric disorders like generalized anxiety disorder (GAD) and major depressive disorder (MDD). Understanding the psychoneuroimmunologic underpinnings of CATIA may inform screening, prevention, and treatment strategies for anxiety-associated disorders.

Therefore, we propose clinical applications particularly for clearly defined vulnerable populations affected by inflammation-induced anxiety. These vulnerable populations could be detected using a “screening & scoring system”, and personalized treatment options could then be applied according to a defined algorithm. Although the literature widely supports the theoretical background of CATIA, the hypothesis is thus far untested and needs further investigation. We outline specific suggestions how this could be achieved in a clinical context.

{"title":"The “conflict avoidance theory of inflammation-induced anxiety” (CATIA): A psychoneuroimmunologic hypothesis","authors":"P.A. Nelles , N. Singewald , B. Sperner-Unterweger , K. Hüfner","doi":"10.1016/j.mehy.2025.111580","DOIUrl":"10.1016/j.mehy.2025.111580","url":null,"abstract":"<div><div>Anxiety and inflammation are complex, interconnected physiological processes. The “Conflict Avoidance Theory of Inflammation-Induced Anxiety” (CATIA) hypothesizes that inflammation-induced anxiety confers an evolutionary advantage by promoting harm-avoidance and recovery-promoting behaviour. Inflammatory cytokines act as signalling molecules to anxiety-related brain regions, primarily limbic structures such as the amygdala, thus influencing decision-making and behaviour. This is archieved by priming these structures for exaggerated fear-responses counteracting conflict engagement, when adaptive physiological readiness is impaired.</div><div>This adaptive mechanism prioritizes recovery and survival during illness or injury. However, in modern contexts, inflammation driven by lifestyle factors or chronic conditions may perpetuate anxiety symptoms, contributing to psychiatric disorders like generalized anxiety disorder (GAD) and major depressive disorder (MDD). Understanding the psychoneuroimmunologic underpinnings of CATIA may inform screening, prevention, and treatment strategies for anxiety-associated disorders.</div><div>Therefore, we propose clinical applications particularly for clearly defined vulnerable populations affected by inflammation-induced anxiety. These vulnerable populations could be detected using a “screening & scoring system”, and personalized treatment options could then be applied according to a defined algorithm. Although the literature widely supports the theoretical background of CATIA, the hypothesis is thus far untested and needs further investigation. We outline specific suggestions how this could be achieved in a clinical context.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"196 ","pages":"Article 111580"},"PeriodicalIF":2.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143158295","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Could site-specific glycation of Von Willebrand factor serve as a biomarker for macrovascular disease in diabetes?

IF 2.1 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2025-01-29 DOI: 10.1016/j.mehy.2025.111572

Esra Seyran

Cardiovascular disease (CVD) is the leading cause of mortality among diabetic patients. Glycation is a non-enzymatic, post translational process where sugars bind to proteins, and it is accelerated in diabetes. Glycation may alter protein structure and function. Von Willebrand Factor (VWF) is a key player in coagulation, and its glycation could potentially exacerbate the pro-thrombotic state associated with diabetes. We hypothesize that glycation of VWF contributes to the progression of macrovascular complications by altering its interactions with key hemostatic partners, such as Factor VIII, platelets (via GPIbα binding), and ADAMTS-13 thereby promoting hypercoagulability and endothelial dysfunction. This hypothesis highlights a functional link between chronic hyperglycemia and macrovascular complications in diabetes. To test this hypothesis, mapping glycation of sites of VWF using mass spectrometry and validating its role as a biomarker using patient-derived samples and high-throughput assays is proposed. If confirmed, this mechanism could provide a novel biomarker for the early detection of high-risk patients and open up new therapeutic targets to manage cardiovascular complications aimed at mitigating cardiovascular disease and improving patient outcomes.

{"title":"Could site-specific glycation of Von Willebrand factor serve as a biomarker for macrovascular disease in diabetes?","authors":"Esra Seyran","doi":"10.1016/j.mehy.2025.111572","DOIUrl":"10.1016/j.mehy.2025.111572","url":null,"abstract":"<div><div>Cardiovascular disease (CVD) is the leading cause of mortality among diabetic patients. Glycation is a non-enzymatic, post translational process where sugars bind to proteins, and it is accelerated in diabetes. Glycation may alter protein structure and function. Von Willebrand Factor (VWF) is a key player in coagulation, and its glycation could potentially exacerbate the pro-thrombotic state associated with diabetes. We hypothesize that glycation of VWF contributes to the progression of macrovascular complications by altering its interactions with key hemostatic partners, such as Factor VIII, platelets (via GPIbα binding), and ADAMTS-13 thereby promoting hypercoagulability and endothelial dysfunction. This hypothesis highlights a functional link between chronic hyperglycemia and macrovascular complications in diabetes. To test this hypothesis, mapping glycation of sites of VWF using mass spectrometry and validating its role as a biomarker using patient-derived samples and high-throughput assays is proposed. If confirmed, this mechanism could provide a novel biomarker for the early detection of high-risk patients and open up new therapeutic targets to manage cardiovascular complications aimed at mitigating cardiovascular disease and improving patient outcomes.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"196 ","pages":"Article 111572"},"PeriodicalIF":2.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143157721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Could body piercing be a cause of rheumatoid arthritis?

IF 2.1 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2025-01-29 DOI: 10.1016/j.mehy.2025.111577

Martin James Seed

Rheumatoid arthritis (RA) can be a chronic disabling condition despite modern immunosuppressive treatments. Better understanding of its aetiology is key to prevention and despite advances in immunogenetic knowledge the environmental triggers of RA remain uncertain. Following exploration of literature pertaining to the epidemiology and immunopathology of RA, the plausibility of a hypothesis that body piercing might have a causal role is presented. Indigenous North American (INA) populations exhibit markedly raised prevalence rates of RA and often have cultural traditions that involve body piercing in a variety of forms. Historical and archaeological evidence of early RA has consistency in timing with evidence of early human body piercing. The incidence of RA in the UK has increased in recent decades in parallel with an increase in frequency and diversity of body piercing behaviour. Body piercing is a form of somatic trauma resulting in a piercing cavity that houses a foreign object (jewellery) with hypothetical potential to stimulate autoreactive immunological processes. If the pierced tissue is mucosa there is potential for dysbiosis and breakdown in tolerance to modified proteins, thought to be an important early event in RA development. Piercing of cartilage has potential to cause autoreactivity to type II collagen and RA. A carefully designed case-control study might either refute or substantiate this hypothesis which could have significant implications for RA prevention.

{"title":"Could body piercing be a cause of rheumatoid arthritis?","authors":"Martin James Seed","doi":"10.1016/j.mehy.2025.111577","DOIUrl":"10.1016/j.mehy.2025.111577","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) can be a chronic disabling condition despite modern immunosuppressive treatments. Better understanding of its aetiology is key to prevention and despite advances in immunogenetic knowledge the environmental triggers of RA remain uncertain. Following exploration of literature pertaining to the epidemiology and immunopathology of RA, the plausibility of a hypothesis that body piercing might have a causal role is presented. Indigenous North American (INA) populations exhibit markedly raised prevalence rates of RA and often have cultural traditions that involve body piercing in a variety of forms. Historical and archaeological evidence of early RA has consistency in timing with evidence of early human body piercing. The incidence of RA in the UK has increased in recent decades in parallel with an increase in frequency and diversity of body piercing behaviour. Body piercing is a form of somatic trauma resulting in a piercing cavity that houses a foreign object (jewellery) with hypothetical potential to stimulate autoreactive immunological processes. If the pierced tissue is mucosa there is potential for dysbiosis and breakdown in tolerance to modified proteins, thought to be an important early event in RA development. Piercing of cartilage has potential to cause autoreactivity to type II collagen and RA. A carefully designed case-control study might either refute or substantiate this hypothesis which could have significant implications for RA prevention.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"196 ","pages":"Article 111577"},"PeriodicalIF":2.1,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143158691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Mitigating recurrent Urinary tract infections using neutrophil activation by a low frequency electromagnetic field exposure: A hypothesis

IF 2.1 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2025-01-27 DOI: 10.1016/j.mehy.2025.111578

Jan J.M. Cuppen , Dick A.W. Janssen , Huub F.J. Savelkoul

This paper hypothesises that activating neutrophils using a low-frequency electromagnetic field (LF-EMF) micro-stimulus could reduce immune delays. In recurrent urinary tract infections (rUTIs) that would mean less symptoms and less need for antibiotics.

Uropathogenic Escherichia coli (UPEC) induces a temporary immune delay, allowing it to multiply to high bacterial load before the immune system responds. UPEC then also establishes an intracellular niche that protects a population of replicating bacteria from arriving phagocytes. A low-cost, low-burden treatment with a subtle electromagnetic stimulus has recently been shown to activate neutrophils in vivo in humans. The same stimulus has been shown in animal and in vitro experiments to immediately increase immune function, reduce mortality and tissue damage and increase vitality with an easy treatment of 30 min per day. We hypothesize that the selected Low Frequency Electromagnetic Field (LF-EMF) treatment will accelerate neutrophil activation and recruitment to the bladder, reducing immune delay. When used early in a UTI episode it can speed up the immune response, can therefore reduce both the maximum ‘size’ of the infection and of the immune response, and thereby reduce disease-symptoms and tissue-damage. By reducing the need for antibiotics, it can also help to mitigate the increase of antibiotic resistance.

{"title":"Mitigating recurrent Urinary tract infections using neutrophil activation by a low frequency electromagnetic field exposure: A hypothesis","authors":"Jan J.M. Cuppen , Dick A.W. Janssen , Huub F.J. Savelkoul","doi":"10.1016/j.mehy.2025.111578","DOIUrl":"10.1016/j.mehy.2025.111578","url":null,"abstract":"<div><div>This paper hypothesises that activating neutrophils using a low-frequency electromagnetic field (LF-EMF) micro-stimulus could reduce immune delays. In recurrent urinary tract infections (rUTIs) that would mean less symptoms and less need for antibiotics.</div><div>Uropathogenic <em>Escherichia coli</em> (UPEC) induces a temporary immune delay, allowing it to multiply to high bacterial load before the immune system responds. UPEC then also establishes an intracellular niche that protects a population of replicating bacteria from arriving phagocytes. A low-cost, low-burden treatment with a subtle electromagnetic stimulus has recently been shown to activate neutrophils <em>in vivo</em> in humans. The same stimulus has been shown in animal and in vitro experiments to immediately increase immune function, reduce mortality and tissue damage and increase vitality with an easy treatment of 30 min per day. We hypothesize that the selected Low Frequency Electromagnetic Field (LF-EMF) treatment will accelerate neutrophil activation and recruitment to the bladder, reducing immune delay. When used early in a UTI episode it can speed up the immune response, can therefore reduce both the maximum ‘size’ of the infection and of the immune response, and thereby reduce disease-symptoms and tissue-damage. By reducing the need for antibiotics, it can also help to mitigate the increase of antibiotic resistance.</div></div>","PeriodicalId":18425,"journal":{"name":"Medical hypotheses","volume":"196 ","pages":"Article 111578"},"PeriodicalIF":2.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143379161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Can human metapneumovirus infection be prevented by exercise?

IF 2.1 4区医学 Q3 MEDICINE, RESEARCH & EXPERIMENTAL

Medical hypotheses

Pub Date : 2025-01-23 DOI: 10.1016/j.mehy.2025.111575

Bogdan-Alexandru Hagiu

引用次数: 0

首页上一页

下一页尾页

类型

全部化学•材料生命科学医学物理工程技术环境•农林材料科学地球科学法学管理学化学环境科学与生态学计算机科学教育学经济学农林科学人文科学生物学数学物理与天体物理心理学综合性期刊其他工业工程理学历史学农学文学信息工程

数据库

全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley

期刊

Medical hypotheses

全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.

﹀